New Role for Grb10 Signaling in the Pancreas

Department of Biology and Biochemistry and Centre for Regenerative Medicine, University of Bath, Bath, U.K.

Corresponding author: Andrew Ward, bssaw{at}bath.ac.uk.

After surgically removing the canine pancreas, Joseph von Mering and Oskar Minkowski linked the pancreas with diabetes for
the first time (1). Their observation led to the use of purified pancreatic extracts to successfully treat diabetic patients some 30 years
later, then to the identification and application of subcutaneous insulin delivery, as well as more recent islet transplantation
therapies (2). Despite these life-saving advances, diabetes is still a global health care problem. However, there remains much to learn
about the mechanisms involved in glucose homeostasis. Insulin receptor signaling is the central molecular pathway and remains
the subject of intense research activity. Mouse knockout models have played a pivotal role in bridging the gap between our
understanding of the relevant molecular mechanisms and glucose homeostasis in the whole animal (3–5).

In this issue, Zhang et al. (6) report on the pancreas-specific disruption of the Grb10 signaling adaptor protein gene. This builds on a long tradition of mouse knockout experiments targeting components of the
insulin-signaling pathway. Seminally, germline or “global” disruption of the insulin receptor (Insr) gene revealed a subtle effect of Insr signaling on fetal growth (7) as well as perinatal lethality due to acute diabetic ketoacidosis (8,9). The physiological effects of gene disruption can be difficult to interpret when they involve such a severe phenotype and/or
when signaling is altered within multiple insulin-sensitive tissues. To circumvent these problems “conditional” or tissue-specific
mouse knockouts can be generated using Cre-lox technology, an approach used to great effect within the glucose homeostasis
field. In a series …